Pharmacological targeting of the protein synthesis mTOR/4E‐BP1 pathway in cancer‐associated fibroblasts abrogates pancreatic tumour chemoresistance

• Published in: EMBO molecular medicine 2015-06, Vol.7 (6), p.735-753
• Main Authors: Duluc, Camille, Moatassim‐Billah, Siham, Chalabi‐Dchar, Mounira, Perraud, Aurélie, Samain, Rémi, Breibach, Florence, Gayral, Marion, Cordelier, Pierre, Delisle, Marie‐Bernadette, Bousquet‐Dubouch, Marie‐Pierre, Tomasini, Richard, Schmid, Herbert, Mathonnet, Muriel, Pyronnet, Stéphane, Martineau, Yvan, Bousquet, Corinne
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - metabolism; Adenocarcinoma - drug therapy; Animals; Antineoplastic Agents - pharmacology; cancer‐associated fibroblasts; Carcinoma, Pancreatic Ductal - drug therapy; Cells, Cultured; chemoresistance; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Disease Models, Animal; Drug Resistance; EMBO03; EMBO28; Fibroblasts - metabolism; Fibroblasts - physiology; Heterografts; Humans; Mice, Nude; pancreatic cancer; pharmacotherapy; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - metabolism; protein synthesis and secretion; Research Article; Somatostatin - analogs & derivatives; Somatostatin - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Treatment Outcome
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404346

Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma‐rich. Cancer‐associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome‐triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E‐BP1 regulatory pathway which we found highly activated in primary cultures of α‐SMA‐positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E‐BP1 pathway and the resultant synthesis of secreted proteins including IL‐6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine‐induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1‐directed pharmacological compounds represents an anti‐stromal‐targeted therapy with promising chemosensitization potential. Synopsis A novel drug association combining current chemotherapies with pharmacological inhibition of the Cancer‐Associated Fibroblast secretome with the somatostatin analogue SOM230 (Pasireotide), effectively reverses chemoresistance in pancreatic cancer. The secretome of pancreatic cancer‐associated fibroblasts critically contributes to stroma‐triggered chemoresistance. Elevated PI3K/mTOR pathway activity in pancreatic α‐SMA‐positive cancer‐associated fibroblasts contributes to high protein synthesis/secretion rates. Inhibition of the protein synthesis mTOR/4E‐BP1 regulatory pathway in pancreatic cancer‐associated fibroblasts, with the novel somatostatin analogue SOM230 (Pasireotide), reverses tumour chemoresistance. SOM230 selectively targets the somatostatin receptor subtype sst1 in pancreatic α‐SMA‐positive cancer‐associated fibroblasts, which is not expressed in pancreatic non‐activated α‐SMA‐negative fibroblasts or cancer cells. The combination of chemotherapy (gemcitabine) and pharmacological inhibition of the cancer‐associated fibroblast secretome provides synergistic chemosensitization and tumour growth breakdown. Graphical Abstract A novel drug association combining current chemotherapies with pharmacological inhibition